Project Summary Polycystic ovary syndrome (PCOS) affects 6-10% of women and related metabolic complications include insulin resistance (IR), diabetes and nonalcoholic fatty liver disease (NAFLD), which all present in adolescence. Despite the high prevalence and gravity of comorbidities associated with PCOS, widely effective therapeutic options are lacking. A better understanding of the pathology underlying PCOS related metabolic disease is critical to inform development of new therapeutics. NAFLD occurs in >50% of girls with PCOS, is one of the best predictors for worsening metabolic disease and is thus a prime target for improving overall health in PCOS. Our preliminary results demonstrate significant IR and high rates of NAFLD and prediabetes in obese girls with PCOS. Further, NAFLD and post-prandial dysglycemia in these girls appear related to upregulated hepatic de novo lipogenesis (DNL), excess free fatty acids (FFA) and inadequate glucagon like peptide-1 (GLP- 1) secretion. When we administered short-duration treatment with a GLP-1 receptor agonist (GLP-1 RA), PCOS girls had lower post-prandial glucose, FFA and markers of DNL. No work has yet been done on the role of longer-term GLP-1 RA in youth with PCOS, who due to the early disease onset are at the highest risk for long term morbidity and mortality. Limited work in adults indicates that GLP-1 RA decreases liver fat in patients with type 2 diabetes and NAFLD and improves glucose and testosterone concentrations in women with PCOS, showing the promise of this therapy, although mechanistic work is lacking. Our central hypothesis is that GLP-1 RA will directly improve hepatic metabolism and decrease substrate delivery in obese girls with PCOS, independent of weight loss. The aims of this application will be performed in the context of a randomized clinical trial in 50 medication-naive obese girls with PCOS. Treatment arms will be intensive dietary counseling or weekly GLP-1 RA exenatide for 16 weeks, with a goal of matching weight loss across treatment arms. We aim to: SA1) lower liver fat with 4 months of GLP-1 RA compared to dietary counseling and SA2) assess changes in hepatic glucose and FFA delivery and probe the unique hepatic mechanisms of early NAFLD in PCOS with stable isotope tracer-assessed DNL and hepatic TCA cycle activity measured non-invasively with isotopomers and 31phosphoprus magnetic resonance spectroscopy (31P MRS). We are uniquely poised to perform this important work as we have successfully enrolled over 100 similar participants in previous trials, are experienced in clinical trials with medications in youth and have an established team of experts in the fields of hepatic metabolism and novel methodologies, including isotope tracers, isotopomer analysis and 31P MRS . The project is innovative in both the approach, with a combination of isotopomer and MRS work, and a unique, high-risk patient population. The results will significantly advance not only the overall mechanistic understanding of NAFLD in obesity, but will also provide the necessary evidence for a new therapeutic option to improve the immediate and long-term health of obese PCOS girls.